Progestogen-anti-progestogen regimens

ABSTRACT

An estrogen-free contraceptive is disclosed which does not have the bleeding-related drawbacks of conventional progestogen-only pills. The invention includes a contraceptive kit comprising a combined means for the simultaneous daily administration of a progestogen and an anti-progestogen. The combined means may be in the form of tablets having a normal contraceptive dose of the progestogen and a low dose of the anti-progestogen.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation of U.S. Ser. No. 09/554,429, filed Jun. 26, 2000, now U.S. patent, which is a national stage entry of PCT/EP98/07221, filed Nov. 10, 1998, designating the United States of America, corresponding to PCT International Publication Number WO 99/25360, the contents of which are incorporated herein in its entirety.

TECHNICAL FIELD

[0002] The invention relates to a contraceptive kit (drug delivery system) comprising means (a) for the daily administration of a progestogen and means (b) for the administration of an anti-progestogen, providing a contraceptive regimen of the estrogen-free, i.e., progestogen-only type.

BACKGROUND

[0003] It has been known for some time that contraception can be achieved by the oral administration of sufficient quantities of a progestogen to a female of child-bearing age. Contraceptive preparations that minimize the incidence of menstrual spotting, break through bleeding, variations in menstrual cycle length and amenorrhea are preferred. It is further preferred to use contraceptive regimens that minimize the amounts of estrogens and progestogens used.

[0004] Preparations that fulfill many of these requirements are disclosed in PCT International Publication Number WO 93/21927, wherein a contraceptive regimen free from estrogens is described, the active, ovulation-inhibiting ingredient being a progestational agent and intermittently an anti-progestogen. The regimen used is a regimen wherein only levonorgestrel is administered as the progestogen, except that on days 1, 30, 60, 90, 120, 150, and 180 a dosage of the anti-progestogen RU 486 is administered. In fact, the regimen is a progestogen-only regimen, interrupted by anti-progestogen administration at the beginning of each cycle. Although this regimen is a considerable improvement over existing regimens comprising estrogens, the bleeding profile is still not perfect since it recurs slowly after an almost bleeding-free interval, and further improvement is therefore desirable.

[0005] “Progestogen-only pills” are a preferred method of contraception for breast-feeding mothers, older women, women for whom estrogen is contraindicated, women who are hypertensive and women who develop migraine headaches when taking a combined pill (i.e., one containing an estrogen and progestogen component). See, e.g., “Contraception for women over the age of 35”, IPPF Medical Bulletin, 22: 3-4 (1988) and P. W. Howie, “The progestogen-only pill”, Brit. J. Obstet. Gynaecol., 92: 1001-2 (1985).

[0006] While different progestogen-only regimens have been described, they are associated with incomplete ovulation inhibition and relatively high failure rates. Vessey, et al. “Progestogen-only oral contraception. Findings in a large prospective study with special reference to effectiveness”, Brit. J. Family Planning, 292: 526-30 (1986). It has been suggested to increase the daily dosage of progestogen in order to induce complete ovulation inhibition; however, such an increase in dosage also increases the frequency of intermenstrual bleeding (i.e., “spotting”) which is clearly not desired. E. Diczfalusy, et al., Progestogens in Therapy, p. 150 (Raven Press, NY 1983).

[0007] Moreover, a high prevalence of functional ovarian cysts has been reported with progestogen only contraceptive regimens which resolve after discontinuation of the progestogen-only contraceptive. Fotherby, K., “The Progestogen-pill”, in: Filshie, et al., eds. Contraception: Science and Practice, pp. 94-108 (1989), and Howie, supra.

[0008] A need exists for a progestogen-only contraceptive regimen which more effectively inhibits ovulation, but does not increase the frequency of intermenstrual bleeding or lead to persistent functional ovarian cysts. The solution to this need by intermittently adding an anti-progestogen needs further elaboration.

SUMMARY OF THE INVENTION

[0009] Surprisingly, a contraceptive regimen satisfying the above need has been found in that a progestogen is administered at a dose sufficient to inhibit ovulation and an anti-progestogen is administered at a dose so as not to affect ovulation, but is sufficient to retain good cycle control and almost completely decreases the amount of spotting and bleeding, i.e., a dose sufficient to prevent irregular bleeding and leads to an improved, more predictable and more acceptable, bleeding pattern as compared to a progestogen-only regimen with or without intermittent anti-progestogen administration.

[0010] The invention thus resides in a contraceptive kit including means (a) for the daily administration of a progestogen and means (b) for the administration of an anti-progestogen, wherein the contraceptive kit is designed to constitute a combined means (c) for the simultaneous daily administration of the progestogen and the anti-progestogen.

[0011] The invention further includes a pharmaceutical product (i.e., the dosage units or the package containing the dosage units), a method of using the product and a process of manufacturing the pharmaceutical product.

[0012] The invention also includes a method of providing contraception involving administering to a woman the above-mentioned regimens.

[0013] Progestogens used with the invention include 3-keto-desogestrel (etonogestrel), desogestrel, gestodene, levonorgestrel, norgestrel and other progestogens known for use in contraception. Desogestrel has the chemical name 13-ethyl-11-methylene18, 19-di-nor-17α-pregn-4-en-20-yn-17-ol, and is the preferred progestogen. Desogestrel is believed to be metabolized in the body into 3-ketodesogestrel (etonogestrel). The dosage units contain 75 μg of desogestrel or 3-ketodesogestrel, or an amount of other progestogens having an effect equivalent to that of 75 μg of desogestrel. Based on practically applied doses, levonorgestrel, desogestrel and 3-keto-desogestrel are relatively equipotent in progestogenic activity. Gestodene is approximately 1.5 times as potent as these compounds and norgestrel is about one-half as potent as levonorgestrel. Other suitable progestogens include progestogens of a newer generation such as Org 30659, known from EP 210 678, the IUPAC name of which is (17α)-17-hydroxy-11-methylene-19-norpregna-4, 15-dien-20-yn-3-one.

[0014] The anti-progestogen can be an inhibitor of progesterone synthesis, such as epostane, azastene or trilostane (Creange, Contraception 24, 289, 1981; Drugs of the Future 7, 661, 1982, van der Spuy, et al., Contraception 35, 111, 1987; U.S. Pat. No. 3,296,255), a progesterone receptor antagonist or any pharmaceutically suitable agent that counteracts the normal biological activity of progesterone, such as antibodies or ligands capable of binding to progestogens or to the progesterone receptor.

[0015] A suitable anti-progestogen is a progesterone receptor antagonist. Such compounds are widely known, e.g., from BP 277 676, EP 289 073, EP 321 010, EP 549 041, EP 582 338, and other publications. Examples of anti-progestogens include RU486, Onapristone, Org 31710 [(6α, 11β, 17β)-11-(4˜dimethylaminophenyl)-6-methyl-4′, 5′-dihydrospiro-[estra-4,9-diene-17,2′-(3 ′H)-furan]-3-one], and Org 33628 [11β,1 7α)-11-(4-acetylphenyl)-17,23-epoxy-19,24-dinorchola-4,9,20-trien-3-one], which are suitable for use in the present invention.

[0016] The main requirement for the daily dose of anti-progestogen is that it is sufficient to prevent irregular bleeding. Preferably, the dose of anti-progestogen is as low as possible. Thus, the daily dose of anti-progestogen is generally chosen to be equivalent to a daily dose of the reference anti-progestogen RU 486 from about 0.05 to 5 mg, and preferably from about 0.1 mg to 2 mg. For most anti-progestogens, the daily dose refers to the daily administration of the corresponding fixed dose. Thus, in the case of Org 33628 and Org 31710 which are somewhat more potent anti-progestogens, the daily dosage amount will typically be in the range from about 0.02 to 4 mg, and preferably from about 0.05 to 2 mg.

[0017] The person of ordinary skill will appreciate that in some cases, it is preferred to adapt the dosage regimen so as to have an exposure to the anti-progestogen which is equivalent with the above daily dose of reference. This can be routinely determined on the basis of the half-life of a given compound. Thus, e.g., Org 33628 and RU 486 (having respective half-lives of approximately 15 hours and 20 hours) administered daily in the above-indicated low dose will lead to a corresponding daily exposure of anti-progestogen, while Org 31710 (having a half-life of 50 hours) administered daily will not effectively lead to daily exposure of a low dose, but to a cumulation of the anti-progestogen level. In order to attain the beneficial effects of the continuous low-dose regimen described above, Org 31710 can be administered every two days, with typical dosage amounts ranging from about 0.05 mg to 5 mg.

[0018] The combined means (c) may comprise any number of daily tablets containing the progestogen and the anti-progestogen. Contrary to the known “progestogen only” or “estrogen free” contraceptives, the package of daily tablets is free from tablets containing solely a progestogen. All tablets comprise a combination of progestogen and anti-progestogen. For practical reasons, it is preferred to provide a kit having at least 28 daily dosage units since this is the normal length of the menstrual cycle.

[0019] It is also possible to incorporate the progestogen and the anti-progestogen into a controlled release device, such as an implant or a vaginal ring. The progestogen and the anti-progestogen may also be incorporated into an IUD (intra uterine device). In principle, the combined means (c) for administering the progestogen and the anti-progestogen may contain two different forms of administration. It is preferred, however, for both substances to be contained in the same dosage units for oral administration, to form the combined means (c). In any event, the combined means may also comprise (alone, or combined with either or both of the progestogen and the anti-progestogen) a single active substance having the required mixed profile of progestogenic and anti-progestogenic properties. Such compounds are known, see, e.g., Sobek, et al. in ENDO′97, page 549 (Poster Sessions of the Endocrine Society, No. P3-452) and Wagner, et al. in Proc. Natl. Acad. Sci. USA, Vol.93, pp. 8739-8744 (1996).

[0020] As used herein, the term “dosage unit” will generally refer to physically discrete units suitable as unitary dosages for humans, each containing a predetermined quantity of active material calculated to produce the desired effect, such as tablets, pills, powders, suppositories, capsules and the like.

[0021] Methods and compositions for making such dosage units are well-known to those skilled in the art. For example, conventional techniques for making tablets and pills containing active ingredients are described in the standard reference, Gennaro, et al., Remington's Pharmaceutical Sciences, (18th ed., Mack Publishing Company, 1990, see especially, Part 8: Pharmaceutical Preparations and Their Manufacture).

[0022] For making dosage units, e.g., tablets, the use of conventional additives, e.g., fillers, colorants, polymeric binders and the like is contemplated. In general, any pharmaceutically acceptable additive which does not interfere with the function of the active compounds can be used in the one or more of the compositions.

[0023] Suitable carriers with which the compositions can be administered include lactose, starch, cellulose derivatives and the like used in suitable amounts. Lactose is a preferred carrier. Mixtures of carriers can also be used.

[0024] A process of manufacturing the kit of the present invention comprises mixing predetermined quantities of progestogen (for instance desogestrel, 3-ketodesogestrel, or mixtures thereof) and anti-progestogen (for instance Org 31710) with predetermined quantities of excipients and converting the mixture into dosage units containing progestogen and anti-progestogen. Preferred kits contain a total of at least 28 of the daily sequential dosage units.

[0025] Converting the mixture into dosage units generally involves molding the mixture into a tablet, filling a capsule with a dried mixture or filling a capsule with a wet mixture.

[0026] A preferred process of manufacturing the pharmaceutical product of the present invention includes incorporating the desired dosages of contraceptive steroid (for example desogestrel, 3-ketodesogestrel, or mixtures thereof) into tablets by techniques such as wet granulation tableting techniques. The package containing the dosage units will generally contain between 28 and 364 (13 times 28) dosage units.

[0027] As to kits containing sequential daily dosage units for oral administration, it will be apparent that the contraceptive kit of the present invention is different from and, in fact, a considerable improvement over the known contraceptive kits of the “progestogen-only” type and those in which, besides a progestogen, an anti-progestogen is administered as well (i.e., more correctly described as an “estrogen-free” regimen). The known contraceptive regimens of this type comprise a multiphasic combination of sequential daily dosage units containing solely the progestogen, as well as sequential daily dosage units containing a progestogen and an anti-progestogen. Contrary to these known regimens, the present invention is characterized in that the regimen does not contain any dosage units having only the progestogen, i.e., the sequential daily dosage units form a continuous, monophasic combination of the progestogen and the anti-progestogen. This leads to the considerable advantage that a much lower amount of anti-progestogen per dosage unit can be administered, while an improved cycle-control is obtained.

[0028] As described herein, the kit of the present invention may also comprise any of the active substances in a form other than that of a daily tablet. It is possible for one active substance, e.g., the progestogen, to be in the form of a daily tablet and the other active substance to be in the form of a sustained-release device, such as an implant, an intra-uterine device or an intravaginal article, such as a vaginal ring, or vice versa. As with daily tablets and other dosage forms, it is preferred that the combined means (c) of the present invention is actually one means, i.e., both the progestogen and the anti-progestogen are released from the same sustained-release device. Notably, the very fact that the contraceptive regimen of the present invention is a continuous, monophasic regimen makes it even better possible, from a technical point of view, to provide other methods of administration.

[0029] Methods of making sustained-release devices such as implants and vaginal rings are known in the art. In this respect, reference is made to Jorge Heller, Drug Delivery in the Plastics Age, in “Innovations in Drug Delivery”, Tom Sam and Jasper Fokkens ed., pages 134-145. For a preferred contraceptive implant, EP 303 306 is referred to. Many designs of vaginal rings releasing two substances are known in the art. The ring-shaped drug delivery system that can be used in the present invention comprises at least one compartment comprising a thermoplastic polymer core containing at least the progestogen and the anti-progestogen in a ratio, by weight that allows a direct release from the core polymer of both compounds in physiologically required amounts. The progestogen is initially dissolved in the core polymer in a relatively low degree of supersaturation, preferably 1 to about 6 times of the amount by weight necessary for obtaining the saturation concentration of the progestogen in the core polymer at 25° C., while the anti-progestogen is initially dissolved in the core polymer in a concentration being lower than that of the progestogenic compound. The at least one compartment may also be surrounded by and a thermoplastic skin (outer layer) which is permeable to allow the progestogen and the anti-progestogen to pass through.

[0030] The invention also pertains to a method of treatment. The method refers to the administration of the anti-progestogen to women who, as a result of using a conventional progestogen-only regimen, suffer from extensive and/or irregular bleeding. In that respect, the invention also includes a method of treating bleeding induced by a progestogen-only contraceptive regimen, wherein an anti-progestogen is administered daily at a dose, calculated as RU 486 equivalent, of from about 0.05 mg to 5 mg, and preferably from about 0.1 to 2 mg, to obtain a better controlled and more predictable bleeding pattern.

[0031] In conjunction with the above, the invention also pertains to a novel medical indication of the daily administration of an anti-progestogen. Thus, the invention also resides in the use of an anti-progestogen for manufacturing a medicament for the treatment (by daily administration of a dose equivalent to a dose of RU 486 of from 0.05 mg to 5 mg) of bleeding resulting from the use of a progestogen-only contraceptive.

[0032] The invention is hereinafter illustrated with reference to the following examples.

DETAILED DESCRIPTION OF THE INVENTION EXAMPLE I

[0033] This example refers to the preparation, in a standard manner, of tablets A-F for once daily administration. The basic composition of the tablets, except for the active substances, is 6.500 mg of corn starch, 1.950 mg of povidone, 0.650 mg of stearic acid, 0.650 mg of colloidal silicone, 0.080 mg of dl-α-tocopherol and 65.000 mg of lactose. The tablets are provided with a coating layer comprising 0.75 mg of hydroxypropylmethylcellulose, 0.15 mg of polyethylene glycol 400, 0.1125 mg of titanium dioxide and 0.1875 mg of talc.

[0034] The tablets constitute combined means for the administration of a progestogen and an anti-progestogen. The amounts of the active substances are as follows (in mg): Tablet Tablet Tablet Tablet Tablet Tablet A B C D E F desogestrel 0.075 0.075 0.075 0.075 0.075 0.075 Org 31710 — 0.5 1.0 1.5 2.0 5.0

[0035] The ovulation-inhibiting substance in each tablet is desogestrel.

EXAMPLE II

[0036] This Example refers to tablets G-L for once daily administration having the same basic composition and coating layer as the tablets of Example I. The amounts of the active substances (in mg) are as follows: Tablet Tablet Tablet Tablet Tablet Table G H I J K L Org 30659 0.075 0.075 0.075 0.075 0.075 0.075 Org 31710 — 0.5 1.0 1.5 2.0 5.0

[0037] The ovulation-inhibiting substance in each tablet is Org 30659.

EXAMPLE III

[0038] This Example refers to a double-blind, placebo controlled, randomized, single center clinical study wherein tablets corresponding to A, C, E, and F are administered to 40 healthy, female volunteers in order to investigate an anti-progestogen at three different dosages in the continuous combined regimen of the present invention. Subjects are studied for a period of 180 days and drug intake starts on the first day of a spontaneous menses. One group of 10 women received tablets A only (in combination with placebo) to serve as a control group. Three groups of 10 women each received tablets A daily and a dose of Org 31710 every other day, the latter doses comprising, per group, 1 mg, 2 mg, and 5 mg, respectively. Daily records include, inter alia, bleeding (or absence of bleeding).

EXAMPLE IV

[0039] This example refers to an ovulation inhibition test with a combined progestogen and anti-progestogen treatment in stumptailed monkey (Macaca Arctoides).

[0040] Experimental design. This test is used to evaluate a combination of a progestogen (desogestrel) and an anti-progestogen (Org 33628) for ovulation-inhibiting activity and effects of the combination on cycle-control following daily oral administration for 21 days. Mature female monkeys, Macaca Arctoides, with at least 2 regular ovulatory estrous cycles (5-20 years of age, 5-17 kg) are treated from cycle day 2-22. Cycle length is monitored by taking daily vaginal swabs with a cotton tipped applicator. The first day of menstrual bleeding is considered to be day 1 of the cycle and the experiment starts with the pre-treatment control cycle. Blood samples are taken twice a week during the treatment cycle and control cycles (pre-treatment and post-treatment) to determine the amount of estradiol and progesterone and to evaluate the occurrence of ovulation.

[0041] Compound doses. Compounds are administered orally. Desogestrel is administered at a dose of 4 μg/kg/day and the anti-progestin Org 33628 is administered at a dose of at 0.5 mg/kg/day or 0.1 mg/kg/day.

[0042] Evaluation of results. The absence of a luteal progesterone peak (levels above 1 ng/ml) during treatment is considered to be predictable for ovulation inhibition. The absence of estradiol levels above 150 pg/mI during treatment is considered to be an indication of inhibited folliculogenesis. 

What is claimed is:
 1. A contraceptive kit comprising: a pharmaceutical product including dosage units, the dosage units comprising a progestogen and an anti-progestogen in daily dosage amounts; and wherein the pharmaceutical product is configured for the simultaneous, continuous daily administration of both the progestogen and the anti-progestogen; wherein the daily dosage amount of the anti-progestogen comprises from about 0.05 mg to about 5 mg of (11β, 17β)-11-[4-dimethylamino)phenyl]-17-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one.
 2. The contraceptive kit of claim 1, wherein: the daily dosage amount of the progestogen is sufficient to inhibit ovulation; and the daily dosage amount of the anti-progestogen does not affect ovulation.
 3. The contraceptive kit of claim 1, wherein the daily dosage amount of anti-progestogen comprises from about 0.1 mg to about 2.0 mg of (11β,17β)-11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one.
 4. The contraceptive kit of claim 1, wherein said kit comprises 28 dosage units.
 5. The contraceptive kit according to claim 1, wherein the dosage units are tablets.
 6. The contraceptive kit of claim 5, wherein: the tablets are configured for oral administration; and the tablets form a continuous, monophasic combination of the progestogen and the anti-progestogen.
 7. The contraceptive kit of claim 1, wherein: the progestogen is selected from the group consisting of desogestrel, gestodene, and (17α)-17-hydroxy-11-methylene-19-norpregna-4,15-dien-20-yn-3-one; and the anti-progestogen is selected from the group consisting of (11β,17β)-11-[4-(Dimethylamino)phenyl]-17-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one, (6α, 11β, 17β)-11-(4-dimethylaminophenyl)-6-methyl-4′,5′-dihydrospiro-[estra-4,9-diene-17,2′-(3′H)-furan]-3-one, and (11β,17α)-11-(4-acetylphenyl)-17,23-epoxy-19,24-dinorchola-4,9,20-trien-3-one.
 8. The contraceptive kit of claim 3, wherein the daily dosage units further comprise a means for releasing the anti-progestogen in a sustained manner.
 9. A contraceptive kit comprising: a pharmaceutical product including tablets, the tablets comprising a progestogen and an anti-progestogen in daily dosage amounts; wherein the tablets include an ovulation-inhibiting amount of the progestogen; wherein the tablets include an amount of the anti-progestogen sufficient to inhibit in vivo anti-progestational activity; and the contraceptive kit is configured to provide the daily administration of the progestogen and the daily administration of the anti-progestogen.
 10. The contraceptive kit of claim 9 wherein: the anti-progestogen is (11β,17β)-11-[4-Dimethylamino)phenyl]-17-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one or (11β,17α)-11-(4-acetylphenyl)-17,23-epoxy-19,24-dinorchola-4,9,20-trien-3-one; each tablet includes the progestogen and the anti-progestogen; and the tablets are for daily administration.
 11. A method for treating bleeding induced by a progestogen-only contraceptive regimen comprising: administering an anti-progestogen daily and continuously at a dose comprising from about 0.05 mg to about 5 mg (11β,17β)-11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one.
 12. The method according to claim 11, wherein the daily dose of anti-progestogen comprises from about 0.1 mg to about 2 mg of (11β,17β)-11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one.
 13. A method of contraception comprising: administering dosage units to a female, the dosage units comprising a progestogen and an anti-progestogen for the simultaneous, continuous daily administration of the progestogen and the anti-progestogen; wherein the daily dosage amount of the anti-progestogen comprises from about 0.05 mg to about 5 mg of (11β,17β)-11-[4-(Dimethylamino)phenyl]-17-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one.
 14. The method according to claim 13, wherein the daily dose of anti-progestogen is from about 0.1 mg to about 2 mg of (11β,17β)-11-[4-(Dimethylamino)phenyl]-17-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one.
 15. The method according to claim 13, wherein: the progestogen is selected from the group consisting of desogestrel, gestodene, and (17α)-17-hydroxy-11-methylene-19-norpregna-4,15-dien-20-yn-3-one; and the anti-progestogen is selected from the group consisting of (11β,17β)-11-[4-(Dimethylamino)phenyl]-17-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one, (6α,11β,17β)-11-(4-dimethylaminophenyl)-6-methyl-4′, 5′-dihydrospiro-[estra-4,9-diene-17,2′-(3′H)-furan]-3-one and (11β,17α)-11-(4-acetylphenyl)-17,23-epoxy-19,24-dinorchola-4,9,20-trien-3-one. 